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OBJECTIVE: Raynaud's phenomenon (RP) affects 3-9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX-503, in the treatment of RP in an ambulatory setting. METHODS: We conducted a multicenter, randomized, placebo-controlled study with a 2-week single-blind run-in period to determine baseline severity, followed by a 4-week double-blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX-503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0-10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run-in period in terms of ambient temperature) compared with baseline. RESULTS: The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX-503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX-503 had a side effect profile similar to that of placebo. CONCLUSION: MQX-503 is well tolerated and more effective than placebo for the treatment of RP. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In systemic sclerosis (SSc) microvascular endothelial cells (MVECs), angiogenesis is blocked by matrix metalloproteinase 12-dependent cleavage of domain 1 of the urokinase-type plasminogen activator receptor (uPAR). Since integrins are associated with the invasive activity of uPAR in angiogenesis, this study was undertaken to show whether full-size and truncated uPAR are differentially associated with integrins and with motor components of the cytoskeleton. METHODS: SSc and normal MVECs were isolated from human skin biopsy specimens and studied by confocal laser scanning microscopy and immunoprecipitation to assess the mechanisms of association of truncated and full-size uPAR with integrins and the actin cytoskeleton. The integrin composition of the MVECs was studied by reverse transcription-polymerasechain reaction. Cell migration and capillary morphogenesis were studied on fibrinogen substrates. Involvement of Rac and Cdc42 was evaluated by Western blotting. RESULTS: Only full-size uPAR showed a connection with the actin cytoskeleton in ECs. This connection was mediated by the uPAR-associated alphaMu- and alphaX-subunits of beta2 integrin, and was absent from SSc MVECs. The cleaved uPAR was not associated with beta2 integrins or with actin. beta3 integrins were associated with both the full-size and cleaved uPAR at focal contacts. The uncoupling of uPAR from beta2 integrins in SSc MVECs impaired the activation of Rac and Cdc42 (thus inhibiting their mediation of uPAR-dependent cytoskeletal rearrangements and cell motility) and blocked the integrin-engagement-delivered signals to the actin cytoskeleton. Invasion and capillary morphogenesis on fibrinogen-coated substrates indicated that ligation of uPAR by uPA empowers the beta2/beta3 integrin-dependent invasion of fibrinogen, and that this system is impaired in SSc MVECs. CONCLUSION: The reduced angiogenic properties of SSc MVECs can be explained by the effects of uPAR truncation and the subsequent loss of the beta2 integrin-mediated connection of uPAR with the actin cytoskeleton in these ECs. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Systemic sclerosis (SSc) is characterized by early endothelial damage evolving to vascular desertification. Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 regulate specific steps in new vessel formation. We undertook this study to determine whether an alteration of the SDF-1/CXCR4 axis might be involved in the pathogenetic mechanisms following ischemic damage during SSc. METHODS: We enrolled 36 SSc patients and 15 controls. Skin biopsy samples were obtained from each subject, and the expression of SDF-1 and CXCR4 was assessed by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analyses. Furthermore, isolated microvascular endothelial cells (MVECs) from 4 patients with diffuse cutaneous SSc (dcSSc) and 3 controls were analyzed for SDF-1 and CXCR4 by confocal laser scanning microscopy, RT-PCR, and Western blotting. RESULTS: SDF-1 and CXCR4 were up-regulated in the skin of patients with early (edematous) SSc, both in the diffuse and limited cutaneous forms, and progressively decreased, with the lowest expression in the latest phases of both SSc subsets. MVECs from patients with dcSSc expressed significantly higher amounts of both isoforms of SDF-1 in the early stage of disease, with a progressive reduction of SDF-1 and CXCR4 in later stages. On the surface of cultured MVECs from patients with dcSSc, SDF-1 and CXCR4 colocalized in polarized areas, suggesting that they are activated in vivo and that they are under strict genetic control to retain capping function. CONCLUSION: Due to its transient expression, SDF-1 could be considered a future therapeutic target to induce new vessel formation in SSc. [ABSTRACT FROM AUTHOR]

Introduction: Evidence has demonstrated that autoimmune diseases tend to coexist at a higher rate than expected, reflecting a common pathogenic pathway. In this study, we investigate the co-occurrence of systemic sclerosis, systemic lupus erythematosus, and Sjogren syndrome in patients with type 1 and type 2 diabetes mellitus., Methods: Our data were obtained using the 2019 Healthcare Cost and Utilization Project, and International Classification of Diseases, 10th Revision diagnosis codes were used to identify patients with systemic sclerosis, systemic lupus erythematosus, lupus nephritis, and Sjogren syndrome, as well as patients with type 1 and type 2 diabetes. We utilized Statistical Analysis System 9.4 for all analyses and included designated weight values to produce nationally representative estimates., Results: The prevalence of systemic sclerosis among patients with type 1 diabetes mellitus and type 2 diabetes mellitus was significantly lower than that for the non-diabetes mellitus control group (0.0007% vs 0.09%, p-value = 0.0064 and 0.01% vs 0.07%, p-value < 0.0001), respectively. Similarly, there was a significant decrease in the prevalence of systemic sclerosis with lung involvement in patients with type 1 and type 2 diabetes mellitus, with a statically significant difference in type 2 diabetes mellitus versus nondiabetic group (0.001% vs 0.006%, p-value < 0.0001). We noted a similar pattern regarding the prevalence of systemic lupus erythematosus and lupus nephritis in patients with type 1 and 2 diabetes. Similarly, there was a significant decrease in the prevalence of Sjogren syndrome in patients with type 1 diabetes and type 2 diabetes., Conclusion: The collected data demonstrates an inverse relation between some autoimmune connective tissue diseases and diabetes. This suggests that these diseases and diabetes mellitus may have different immune pathogenesis. There was also a significantly lower incidence of organ complications such as lupus nephritis and systemic sclerosis lung disease among patients with diabetes, suggesting that diabetes and treatment of diabetes may alter the clinical expression of these disorders., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

To discuss what is currently known about myocarditis in the context of major connective tissue diseases, including Systemic lupus erythematosus, Rheumatoid Arthritis, Sjogren, Dermato-myositis and Polymyositis, Systemic Sclerosis, and Mixed connective tissue disease. Variability exists between studies regarding the incidence of myocarditis in connective tissue diseases, which is hypothesized to be the result of its subclinical course in most cases. Extensive gaps of knowledge exist in the field of pathophysiology. Although endomyocardial biopsy remains to be the gold standard for diagnosis, the advancement in non-invasive modalities such as cardiac MRI, echocardiography, and nuclear medicine has allowed for earlier and more frequent detection of myocarditis. A lack of treatment guidelines was found across the different connective tissue diseases. Most of the literature available revolved around myocarditis in the context of Systemic lupus erythematosus. Numerous recent studies were published that contributed to advancements in diagnosis and treatment however, there remains a lack of diagnostic and treatment guidelines., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD)., Methods: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification., Results: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration., Conclusions: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Systemic sclerosis (SSc) is a rare, complex, connective tissue disorder. Interstitial lung disease (ILD) is common in SSc, occurring in 35-52% of patients and accounting for 20-40% of mortality. Evolution of therapeutic options has resulted in a lack of consensus on how to manage this condition. This Delphi study was initiated to develop consensus recommendations based on expert physician insights regarding screening, progression, treatment criteria, monitoring of response, and the role of recent therapeutic advances with antifibrotics and immunosuppressants in patients with SSc-ILD., Methods: A modified Delphi process was completed by pulmonologists (n = 13) and rheumatologists (n = 12) with expertise in the management of patients with SSc-ILD. Panelists rated their agreement with each statement on a Likert scale from - 5 (complete disagreement) to + 5 (complete agreement). Consensus was predefined as a mean Likert scale score of ≤  - 2.5 or ≥  + 2.5 with a standard deviation not crossing zero., Results: Panelists recommended that all patients with SSc be screened for ILD by chest auscultation, spirometry with diffusing capacity of the lungs for carbon monoxide, high-resolution computed tomography (HRCT), and/or autoantibody testing. Treatment decisions were influenced by baseline and changes in pulmonary function tests, extent of ILD on HRCT, duration and degree of dyspnea, presence of pulmonary hypertension, and potential contribution of reflux. Treatment success was defined as stabilization or improvement of signs or symptoms of ILD and functional status. Mycophenolate mofetil was identified as the initial treatment of choice. Experts considered nintedanib a therapeutic option in patients with progressive fibrotic ILD despite immunosuppressive therapy or patients contraindicated/unable to tolerate immunotherapy. Concomitant use of nintedanib with MMF/cyclophosphamide can be considered in patients with advanced disease at initial presentation, aggressive ILD, or significant disease progression. Although limited consensus was achieved on the use of tocilizumab, the experts considered it a therapeutic option for patients with early SSc and ILD with elevated acute-phase reactants., Conclusions: This modified Delphi study generated consensus recommendations for management of patients with SSc-ILD in a real-world setting. Findings from this study provide a management algorithm that will be helpful for treating patients with SSc-ILD and addresses a significant unmet need., (© 2023. The Author(s).)

Since the start of the global pandemic caused by coronavirus disease 2019 (COVID-19), there have been numerous reports of autoimmune and rheumatological disorders developing after infection with SARS-CoV-2. To date, there has been only one reported case of systemic sclerosis (SSc) developing after SARS-CoV-2 infection. Here, we present another case of SSc developing after infection with SARS-CoV-2. A 48-year-old female with past medical history of anxiety and depression presented to the rheumatology clinic after being referred for further evaluation of abnormal labs, Raynaud's phenomenon, and other concerning symptoms. Shortly after hospitalization for COVID-19 pneumonia, she began experiencing symptoms that included fatigue, xerostomia, dysphagia, bilateral lower extremity weakness, dyspnea with exertion, unintentional weight loss, and diffuse skin hyperpigmentation. Labs ordered shortly before presentation were significant for antinuclear antibody (ANA) titer > 1:1280. Physical exam was remarkable for puffy fingers, sclerodactyly of the fingers, diffuse skin hyperpigmentation, and abnormal nailfold capillaries. Anti-RNA polymerase III, anti-Scl-70, anti-centromere, anti-SSA, anti-SSB, anti-Smith, and anti-Smith/RNP antibodies were all negative. BNP, aldolase, and serum myoglobin levels were within normal limits while creatine phosphokinase level was slightly decreased. Pulmonary function testing showed reduced diffusion capacity with normal lung mechanics and volumes. High-resolution CT scan of the chest showed interstitial lung disease, with findings suggestive of nonspecific interstitial pneumonia. Transthoracic echocardiogram showed mild elevation of right ventricular systolic pressure, but pulmonary hypertension was not found on right heart catheterization. Esophagogastroduodenoscopy (EGD) with biopsy performed for evaluation of esophageal dysphagia showed sliding hiatal hernia, irregular Z-line, and gastric hyperemia. Biopsy of the distal esophagus was consistent with Barrett's esophagus. The patient was diagnosed with SSc according to the 2013 American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) classification criteria for SSc. She is currently being treated with mycophenolate mofetil, amlodipine, methotrexate, and prednisone., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Chandra et al.)

Background: The etiology of systemic sclerosis is not clear, but there is evidence suggesting a critical role for epigenetic alterations in disease pathogenesis and clinical expression. We sought, in this study, to characterize the genome-wide DNA methylation signature in systemic sclerosis microvascular endothelial cells., Methods: We performed a genome-wide DNA methylation study in microvascular endothelial cells derived from seven diffuse cutaneous systemic sclerosis patients compared to seven age-, sex-, and ethnicity-matched healthy controls. We paired matched samples on Illumina HumanMethylation450 (three diffuse cutaneous systemic sclerosis microvascular endothelial cells and three controls), and reproduced the results in an independent set of matched patient and controls using Illumina Infinium MethylationEPIC (four diffuse cutaneous systemic sclerosis patients and four controls) to identify differentially methylated genes., Results: We identified 71,353 differentially methylated CpG sites in systemic sclerosis microvascular endothelial cells using Infinium MethylationEPIC microarray in the first group (0.081% of representative probes) and 33,170 CpG sites in the second group using HumanMethylation450 microarray (0.073% of representative probes) in diffuse cutaneous systemic sclerosis microvascular endothelial cells. Among the two groups of subjects, we identified differential methylation of 2455 CpG sites, representing 1301 genes. Most of the differentially methylated CpG sites were hypermethylated (1625 CpG), corresponding to 910 genes. Common hypermethylated genes in systemic sclerosis microvascular endothelial cells include NOS1, DNMT3A, DNMT3B, HDAC4 , and ANGPT2. We also identified hypomethylation of IL17RA, CTNNA3, ICAM2 , and SDK1 in systemic sclerosis microvascular endothelial cells. Furthermore, we demonstrate significant inverse correlation between DNA methylation status and gene expression in the majority of genes evaluated. Gene ontology analysis of hypermethylated genes demonstrated enrichment of genes involved in angiogenesis ( p = 0.0006). Pathway analysis of hypomethylated genes includes genes involved in vascular smooth muscle contraction ( p = 0.014) and adherens junctions ( p = 0.013)., Conclusion: Our data suggest the presence of significant genome-wide DNA methylation aberrancies in systemic sclerosis microvascular endothelial cells, and identify novel affected genes and pathways in systemic sclerosis microvascular endothelial cells., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

In patients with SSc, the coexistence of ANCA-associated vasculitis (SSc-AAV) has been reported to be associated with a severe disease course, including significant pulmonary and renal involvement. The presence of ANCA is not uncommon in patients with SSc, and therefore clinicians must maintain a high index of clinical suspicion about SSc-AAV. p-ANCA and anti-myeloperoxidase antibodies are the most common antibodies observed. Patients typically present with clinical features of microscopic polyangiitis or renal-limited vasculitis. There are multiple areas of potential interaction in the pathogenesis of SSc and AAV, which can exacerbate/compound vascular disease. In addition, similar patterns of major internal organ involvement (e.g. lung and kidneys) are seen in both conditions. We highlight a diagnostic approach to SSc-AAV and the paucity of data to inform management. As such, SSc-AAV is typically treated as per isolated AAV, which can potentially be hazardous in patients with SSc (e.g. due to the association between high-dose steroid and scleroderma renal crisis). We propose that this rare clinical entity warrants rigorous investigation, including definition of a therapeutic strategy to ameliorate the potentially devastating combination of pathologies in SSc-AAV., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To review similarities between COVID-19 and systemic sclerosis (SSc) early vasculopathy to provide novel insights into both diseases., Methods: A narrative review of the literature supplemented with expert opinion., Results: There is clear evidence that the endothelium is at the centre stage in SSc and COVID-19, with endothelial cell activation/injury and dysfunction creating the crucial evolving step in the pathogenesis of both diseases. The angiotensin system has also been implicated in the early stages of both COVID-19 and SSc. Autoptic studies provide novel insights into the effects of SARS-CoV-2 on the endothelium. Normal endothelium and endothelial dysfunction in COVID-19 and SSc are discussed. It is debated whether SARS-CoV-2 infection triggers autoimmunity with production of autoantibodies which is of mechanistic interest because other viral illnesses are potentially involved in endothelial dysfunction and in SSc pathogenesis., Conclusion: COVID-19 is due to a direct assault of SARS-CoV-2 on the vascular system as an acute infection, whereas SSc remains a chronic/sub-acute autoimmune disease of largely unknown etiology Further study and exploration of the SARS-CoV-2 pathogenic mechanisms might provide further useful milestones in the understanding of the early SSc pathogenesis., (Copyright © 2021. Published by Elsevier B.V.)

Impaired angiogenesis in scleroderma (SSc) is a critical component of SSc pathology. MicroRNA-126 (miR-126) is expressed in endothelial cells (MVECs) where it regulates VEGF responses by repressing the negative regulators of VEGF, including the sprouty-related protein-1 (SPRED1), and phosphoinositide-3 kinase regulatory subunit 2 (PIK3R2). MVECs were isolated from SSc skin and matched subjects (n = 6). MiR-126 expression was measured by qPCR and in situ hybridization. Matrigel-based tube assembly was used to test angiogenesis. MiR-126 expression was inhibited by hsa-miR-126 inhibitor and enhanced by hsa-miR-126 Mimic. Epigenetic regulation of miR-126 expression was examined by the addition of epigenetic inhibitors (Aza and TSA) to MVECs and by bisulphite genomic sequencing of DNA methylation of the miR-126 promoter region. MiR-126 expression, as well as EGFL7 (miR-126 host gene), in SSc-MVECs and skin, was significantly down-regulated in association with increased expression of SPRED1 and PIK3R2 and diminished response to VEGF. Inhibition of miR-126 in NL-MVECs resulted in reduced angiogenic capacity, whereas overexpression of miR-126 in SSc-MVECs resulted in enhanced tube assembly. Addition of Aza and TSA normalized miR-126 and EGFL7 expression levels in SSc-MVECs. Heavy methylation in miR-126/EGFL7 gene was noted. In conclusion, these results demonstrate that the down-regulation of miR-126 results in impaired VEGF responses., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)